Described is a method of sanitizing animal carcasses using aqueous streams having an antimicrobial composition added to the stream. Preferably, the antimicrobial composition includes a mixture of one or more carboxylic acids having up to 18 carbon atoms and one or more peroxycarboxylic acids having up to 12 carbon atoms, preferably a mixture of a C2-C4 peroxycarboxylic acid and a C8-C12 peroxycarboxylic acid. Also described is a novel antimicrobial composition adapted for sanitizing animal carcasses containing a mixture of one or more C2-C4 peroxycarboxylic acids and one or more C8-C12 peroxycarboxylic acids and an alpha-hydroxy mono- or dicarboxylic acid.

This invention generally relates to compositions and processes for cleaning or sanitizing animal carcasses during meat packing or preparation. More specifically, this invention relates to antimicrobial compositions and processes for cleaning and sanitizing animal carcasses through direct contact between the carcass and the treatment The nature of the contact between the carcass and the antimicrobial compositions improves antimicrobial properties. The compositions and methods reduce microbial populations and do not affect the appearance, smell or taste of the carcass meat.
The cleaning of carcasses in the preparation of any food product can be an unsanitary and time consuming task. Further, without a cleaning routine which follows an ordered process of steps to completely sanitize carcass meat, any number of problems may arise. Carcass meat may retain pathogens or infectious microbes (E. coli) or become increasingly more contaminated if viscera is allowed to rupture or is not properly removed. Further, incomplete cleaning of the carcass meat may also result in the presence of infectious microbes making the meat unsuitable for consumption.
PURAC(copyright) is a natural lactic acid produced by fermentation from sugar. It has a mild acid taste and is widely used in the food industry as an acidulant. PURAC(copyright) is an effective decontaminating agent for use with poultry, beef and pork carcasses and slaughter by-products. PURAC(copyright) is most effective at a use concentration of between 1 and 2 percent, and can be used at several different points in the slaughter line. Application immediately after hide removal reduces the amount of microorganisms entering subsequent processing steps, while treatments after evisceration and prior to chilling have the greatest residual effects. Mountney et al. also discuss the use of lactic acid to lower bacterial counts and otherwise preserve poultry in xe2x80x9cAcids As Poultry Meat Preservativesxe2x80x9d in Poultry Science, 44: 582, 1965. Blankenship et al. discussed the destruction of Salmonella contaminates on fajita chicken meat in xe2x80x9cEfficacy of Acid Treatment Plus Freezing To Destroy Salmonella Contaminates Of Spice Coated Chicken Fajita Meatxe2x80x9d in Poultry Science, Vol. 69, Supp., 1990, p. 20. Adams et al. discuss the use of propylene glycol, sodium lactate, and lactic acid in chill water to reduce salmonella contamination of processed broilers. (See, Effects of Various Chill Water Treatments on Incidents and Levels of Salmonella on Processed Carcasses, Department of Animal and Poultry Sciences, University of Arkansas, Fayetteville). Izat et al. discuss the effects of lactic acid on commercial broiler carcasses in reducing salmonella counts in Poultry Science, Vol. 69, Supp. 1990, p. 152; Journal of Quality, Vol. 13, 1990 p. 295-306; and Journal of Food Protection, Vol. 52, No. 9, pp. 670-673, Sept. 1989. Avens et al. discuss the pasteurization of turkey carcasses and the reduction of salmonella using lactic acid in Poultry Science, Vol. 51, 1972, p. 178 1. Mulder et al. in 1987 Poultry Science 66:1555-1557 reports a study of treating broiler carcasses with lactic acid, 1-cysteine and hydrogen peroxide. The treatment with lactic acid and hydrogen peroxide resulted in a 4-log cycle reduction in colony forming units of Salmonella typhimurium. Nevertheless, use of lactic acid resulted in a slightly changed color of the carcasses and all the treatments with hydrogen peroxide resulted in bleached and bloated carcasses.
Although peroxycarboxylic acids are known to be used for cleaning and sanitizing equipment and other surfaces, they have not been reported for cleaning and sanitizing animal carcasses. Holzhauer et al., U.S. Pat. No. 5,435,808, describes curing of animal hides with an acetic acid, peroxyacetic acid, hydrogen peroxide, and phosphoric acid combination. The heightened concerns of consumers over the organoleptic purity and safety of meat products, concerns over the environmental and organoleptic impact of many antimicrobial agents currently available, as well as the stringent economies of the meat and poultry industry have resulted in an ongoing need for carcass sanitizing compositions and processes which provide increased sanitization with organoleptic and environmental purity.
Accordingly the present invention, in a first aspect, provides a method of treating animal carcasses to obtain a reduction by at least one log10 in surface microbial population which method includes the step of treating said carcass with an antimicrobial composition comprising an effective antimicrobial amount comprising at least 2 parts per million (ppm, parts by weight per each one million parts) of one or more peroxycarboxylic acids having up to 12 carbon atoms and an effective antimicrobial amount comprising at least 20 ppm of one or more carboxylic acids having up to 18 carbon atoms to reduce the microbial population.
A second aspect of the invention is an antimicrobial composition adapted for cleaning and sanitizing animal carcasses which contains about 0.5 weight percent (wt-%) to about 20 wt-% of a mixture of one or more peroxycarboxylic acids having from 2-4 carbon atoms, and one or more peroxycarboxylic acids having from 8-12 carbon atoms, from about 0.5 wt-% to about 60 wt-% of an alpha-hydroxy mono or dicarboxylic acid having 3-6 carbon atoms, an effective amount of a sequestrant and an effective amount of a hydrotrope.
A third preferred aspect of the present invention is an antimicrobial composition adapted for treating animal carcasses consisting of a mixture of peroxyacetic and peroxyoctanoic acid in a ratio of about 10:1 to about 1:1, from about 0.1 to about 10 wt-% of lactic acid, from about 4 wt-% to about 10 wt-% of hydrogen peroxide and from about 0.5 wt-% to about 1.5 wt-% of a sequestering agent.
A fourth aspect of the present invention involves a method of treating an animal carcass to reduce a microbial population in resulting cut meat, the method comprising the steps of spraying an aqueous antimicrobial treatment composition onto said carcass at a pressure of at least 50 psi at a temperature of up to about 60xc2x0 C. resulting in a contact time of at least 30 seconds, the antimicrobial composition comprising an effective antimicrobial amount comprising least 2 ppm of one or more carboxylic acid, peroxycarboxylic acid or mixtures thereof; and achieving at least a one log10 reduction in the microbial population.
A fifth aspect of the present invention involves a method of treating an animal carcass to reduce a microbial population in resulting cut meat, the method comprising the steps of placing the carcass in a chamber at atmospheric pressure; filling the chamber with condensing steam comprising an antimicrobial composition for a short duration; and quickly venting and cooling the chamber to prevent browning of the meat carcass; wherein the duration of the steam thermal process may be from about 5 seconds to about 30 seconds and the chamber temperature may reach from about 50xc2x0 C. to about 93xc2x0 C.
The antimicrobial composition can be applied in various ways to obtain intimate contact with each potential place of microbial contamination. For example, it can be sprayed on the carcasses, or the carcasses can be immersed in the composition. Additional methods include applying a foamed composition and a thickened or gelled composition. Vacuum and or light treatments can be included, if desired, with the application of the antimicrobial composition. Thermal treatment can also be applied, either pre-, concurrent with or post application of the antimicrobial composition. We have found a preferred spray method for treating carcasses with compositions of the invention involving spraying the carcass with an aqueous spray at a temperature less than about 60xc2x0 C. at a pressure of about 50 to 500 psi gauge wherein the spray comprises an effective antimicrobial amount of a carboxylic acid, an effective antimicrobial amount of a peroxycarboxylic acid or mixtures thereof. These sprays can also contain an effective portion of a peroxy compound such as hydrogen peroxide and other ingredients such as sequestering agents, etc. We have found that the high pressure spray action of the aqueous treatment removes microbial populations by combining the mechanical action of the spray with the chemical action of the antimicrobial materials to result in a surprisingly improved reduction of such populations on the surface of the carcass. All pressures are psig (or psi gauge). Differentiation of antimicrobial xe2x80x9c-cidalxe2x80x9d or xe2x80x9c-staticxe2x80x9d activity, the definitions which describe the degree of efficacy, and the official laboratory protocols for measuring this efficacy are important considerations for understanding the relevance of antimicrobial agents in compositions. Antimicrobial compositions may effect two kinds of microbial cell damages. The first is a truly lethal, irreversible action resulting in complete microbial cell destruction or incapacitation. The second type of cell damage is reversible, such that if the organism is rendered free of the agent, it can again multiply. The former is termed bacteriocidal and the latter, bacteriostatic. A sanitizer and a disinfectant are, by definition, agents which provide antibacterial or bacteriocidal activity and achieve at least a five fold reduction (i.e., a five log 10 reduction) in microbial populations after a 30 second contact time (see AOAC method 960.09).
In contrast, a preservative is generally described as an inhibitor or bacteriostatic composition that simply retards growth in a reversible mode. For the purpose of this patent application, successful microbial reduction is achieved when the microbial populations are reduced by one logo. In this industry, the one log10 microbial population reduction is the minimum acceptable for the processes. Any increased reduction in microbial population is an added benefit that provides higher levels of protection for processed carcass meat.
The invention is a process for sanitizing animal carcasses through treatment with aqueous streams containing an antimicrobial composition. The dip or spray methods used for carcass cleaning as well as sanitizing animal carcasses generally include an effective antimicrobial concentration of one or more carboxylic acids and one or more peroxycarboxylic acids.
A. The Sanitizing Composition
The sanitizing composition used in the method of the invention generally contains one or more carboxylic acids and one or more peroxycarboxylic acids with a peroxygen compound such as H2O2. Typically, however, the composition contains one or more carboxylic acids, an oxidizer, and one or more peroxycarboxylic acids depending on equilibrium. Commonly, the peroxycarboxylic acid material can be made by oxidizing a carboxylic acid directly to the peroxycarboxylic acid material which is then solubilized in the aqueous rinse agent compositions of the invention. Further, the materials can be made by combining the unoxidized acid with a peroxygen compound such as hydrogen peroxide to generate the peracid in situ prior to blending the peroxycarboxylic acid with other constituents. The compositions of the invention comprises blends of the carboxylic acid and percarboxylic acid along with other components including a peroxy source such as hydrogen peroxide. Once blended and applied the compositions can change due to interactions between the blended materials and due to interactions in the use locus. For example, the salt component can exchange and become associated with free acids and the peroxy source can oxidize oxidizable materials. The anti-microbial properties arise from the blend of an acid material and a peracid material. The modification post blending and application do not change the invention.
A carboxylic acid is an organic acid (Rxe2x80x94COOH) which contains an aliphatic group and one or more carboxyl groups. A carboxyl group is represented by xe2x80x94COOH, and is usually located at a terminal end of the acid. The aliphatic group can be a substituted or unsubstituted group. Common aliphatic substituents include xe2x80x94OH, xe2x80x94OR, xe2x80x94NO2, halogen, and other substituents common on these groups. An example of a simple carboxylic acid is acetic acid, which has the formula CH3COOH. A peroxycarboxylic acid is a carboxylic acid which has been oxidized to contain a terminal xe2x80x94COOOH group. The term peroxy acid is often used to represent a peroxycarboxylic acid. An example of a simple peroxy acid is peroxyacetic acid, which has the formula CH3COOOH.
Generally when the peroxycarboxylic acid is formulated in accordance with the invention a monocarboxylic acid, such as acetic acid, is combined with an oxidizer such as hydrogen peroxide. The result of this combination is a reaction producing a peroxycarboxylic acid, such as peroxyacetic acid, and water. The reaction follows an equilibrium in accordance with the following equation:
H2O2+CH3COOH⇄CH3COOOH+H2O
wherein the pKeq is 1.7.
The importance of the equilibrium results from the presence of hydrogen peroxide, the carboxylic acid and the peroxycarboxylic acid in the same composition at the same time. Because of this equilibrium, a mixture of carboxylic acid and peroxycarboxylic acid can be combined in water without adding hydrogen peroxide. If permitted to approach equilibrium, the mixture will evolve hydrogen peroxide. This combination provides enhanced sanitizing with none of the deleterious environmental or organoleptic effects of other sanitizing agents, additives, or compositions.
The first constituent of the composition used in the method of the invention includes one or more carboxylic acids. Generally, carboxylic acids have the formula Rxe2x80x94COOH wherein the R may represent any number of different groups including aliphatic groups, alicyclic groups, aromatic groups, heterocyclic groups, all of which may be saturated or unsaturated. Carboxylic acids also occur having one, two, three, or more carboxyl groups. Aliphatic groups can be further differentiated into three distinct classes of hydrocarbons. Alkanes (or paraffins) are saturated hydrocarbons. Alkenes (or olefins) are unsaturated hydrocarbons which contain one or more double bonds and alkynes (or acetylenes) are unsaturated hydrocarbons containing one or more highly reactive triple bonds. Alicyclic groups can be further differentiated into three distinct classes of cyclic hydrocarbons. Cycloparaffins are saturated cyclic hydrocarbons. Cycloolefins are unsaturated cyclic hydrocarbons which contain one or more double bonds while cycloacetylenes are unsaturated cyclic hydrocarbons containing one or more highly reactive triple bonds. Aromatic groups are defined as possessing the unsaturated hydrocarbon ring structure representative of benzene. Heterocyclic groups are defined as 5 or 6 member ring structures wherein one or more of the ring atoms are not carbon. An example is pyridine, which is essentially a benzene ring with one carbon atom replaced with a nitrogen atom.
Carboxylic acids have a tendency to acidify aqueous compositions in which they are present as the hydrogen atom of the carboxyl group is active and may appear as a cation. The carboxylic acid constituent within the present composition when combined with aqueous hydrogen peroxide generally functions as an antimicrobial agent as a result of the presence of the active hydrogen atom. Moreover, the carboxylic acid constituent within the invention maintains the composition at an acidic pH. The composition of the invention can utilize carboxylic acids containing as many as 18 carbon atoms. Examples of suitable carboxylic acids include formic, acetic, propionic, butanoic, pentanoic, hexanoic, heptanoic, octanoic, nonanoic, decanoic, undecanoic, dodecanoic, lactic, maleic, ascorbic, citric, hydroxyacetic, neopentanoic, neoheptanoic, neodecanoic, oxalic, malonic, succinic, glutaric, adipic, pimelic and subric acid.
Carboxylic acids which are generally useful are those having one or two carboxyl groups where the R group is a primary alkyl chain having a length of C2 to C5 and which are freely water soluble. The primary alkyl chain is that carbon chain of the molecule having the greatest length of carbon atoms and directly appending carboxyl functional groups. Especially useful are mono- and dihydroxy substituted carboxylic acids including alpha-hydroxy substituted carboxylic acid. A preferred carboxylic acid is acetic acid, which produces peroxyacetic acid to increase the sanitizing effectiveness of the materials. Acetic acid has the structure of the formula:
An especially preferred -hydroxy-monocarboxylic acid is lactic acid, also known as 2-hydroxypropionic acid, which is a naturally occurring organic acid. Lactic acid has a molecular weight of 90.08 and is soluble in water, alcohol, acetone, ether and glycerol. Lactic acid occurs naturally and may be produced by fermentation. Alternatively, lactic acid may be synthesized.
Lactic Acid has the Structure of the Formula
The concentration of xcex1-hydroxy-mono-or di-carboxylic acid useful in the present invention generally ranges from about 0.5 wt-% to about 60 wt-%, preferably about 1 wt-% to about 20 wt-%, and most preferably from about 2 wt-% to about 10 wt-%. This concentration range of lactic acid is preferred for reasons of optimal acidity within the composition, as well as for the optimal antimicrobial efficacy which it brings to the antimicrobial system.
Reducing the concentration of lactic acid in comparison to any given concentration of hydrogen peroxide will essentially reduce the antimicrobial activity of the composition. Moreover, reducing the concentration of lactic acid may result in an increase in the pH of the composition and accordingly raise the potential for decreased antimicrobial activity. In sharp contrast, increasing the concentration of lactic acid within the present composition may tend to increase the antimicrobial activity of the composition. Furthermore, increasing the concentration of lactic acid in the composition of the present invention will tend to decrease the pH of the composition. Preferably, the pH of the present composition will be 4 or less with a generally preferred pH in the composition being between 1.5 and 3.75, and a pH between about 2 and 3.5 being most preferred.
Generally, the concentration of carboxylic acid within the composition used in the process of the invention ranges from about 0.5 wt-% to about 60 wt-%, preferably from about 10 wt-% to about 60 wt-%, and most preferably from about 20 wt-% to about 50 wt-%.
Another principle component of the antimicrobial composition of the invention is an oxidized carboxylic acid. This oxidized or peroxycarboxylic acid provides heightened antimicrobial efficacy when combined with hydrogen peroxide and the monocarboxylic acid in an equilibrium reaction mixture. Peroxycarboxylic acids generally have the formula R(CO3H)n, where R is an alkyl, arylalkyl, cycloalkyl, aromatic or heterocyclic group, and n is one or two and named by prefixing the parent acid with peroxy. An alkyl group is a paraffinic hydrocarbon group which is derived from an alkane by removing one hydrogen from the formula. The hydrocarbon group may be either linear or branched, having up to 12 carbon atoms. Simple examples include methyl (CH3) and ethyl (CH2CH3). An arylalkyl group contains both aliphatic and aromatic structures. A cycloalkyl group is defined as a cyclic alkyl group.
While peroxycarboxylic acids are not very stable, their stability generally increases with increasing molecular weight. Thermal decomposition of these acids may generally proceed by free radical and nonradical paths, by photodecomposition or radical-induced decomposition, or by the action of metal ions or complexes. Peroxycarboxylic acids may be made by the direct, acid catalyzed equilibrium action of 30-98 wt-% hydrogen peroxide with the carboxylic acid, by autoxidation of aldehydes, or from acid chlorides, acid anhydrides, or carboxylic anhydrides with hydrogen or sodium peroxide.
Peroxycarboxylic acids useful in this invention include peroxyformic, peroxyacetic, peroxypropionic, peroxybutanoic, peroxypentanoic, peroxyhexanoic, peroxyheptanoic, peroxyoctanoic, peroxynonanoic, peroxydecanoic, peroxyundecanoic, peroxydodecanoic, peroxylactic, peroxymaleic, peroxyascorbic, peroxyhydroxyacetic, peroxyoxalic, peroxymalonic, peroxysuccinic, peroxyglutaric, peroxyadipic, peroxypimelic and peroxysubric acid and mixtures thereof. These peroxycarboxylic acids have been found to provide good antimicrobial action with good stability in aqueous streams. In a preferred embodiment, the composition of the invention utilizes a combination of several different peroxycarboxylic acids. Preferably, the composition includes one or more small C2-C4 peroxycarboxylic acids and one or more large C8-C12 peroxycarboxylic acids. Especially preferred is an embodiment in which the small peroxycarboxylic acid is peroxyacetic acid and the large acid is either peroxyoctanoic acid or peroxydecanoic acid.
Peroxyacetic acid is a peroxycarboxylic acid with a structure as given the formula:
wherein the peroxy group, xe2x80x94Oxe2x80x94Oxe2x80x94, is considered a high energy bond. Generally, peroxyacetic acid is a liquid having an acrid odor and is freely soluble in water, alcohol, ether, and suliric acid. Peroxyacetic acid may be prepared through any number of means known to those of skill in the art including preparation from acetaldehyde and oxygen in the presence of cobalt acetate. A 50% solution of peroxyacetic acid may be obtained by combining acetic anhydride, hydrogen peroxide and sulfuric acid. Other methods of formulation of peroxyacetic acid include those disclosed in U.S. Pat. No. 2,833,813, which is incorporated herein by reference.
Peroxyoctanoic acid has the structure of the formula:
Peroxydecanoic acid has the structure of the formula:
The preferred peroxycarboxylic acid materials of the invention can be used to increase the sanitizing effectiveness of the materials. When a blended acid is used, the peroxycarboxylic acid is blended in proportions that range from about 10:1 to about 1:1 parts of C2-C4 peroxycarboxylic acid per part of C8-C12 peroxycarboxylic acid. Preferably, peroxyacetic acid is used at a ratio of about 8 parts per part of peroxyoctanoic acid.
The above sanitizer material can provide antibacterial activity to the rinse aid sanitizers of the invention against a wide variety of microorganisms such as gram positive (for example, Staphylococcus aureus) and gram negative (for example, Escherichia coli) microorganisms, yeast, molds, bacterial spores, viruses, etc. When combined, the above peroxy acids can have enhanced activity compared to the low molecular weight peroxy acids alone.
Generally, the concentration of peroxycarboxylic acid within the composition used in the process of the invention ranges from about 0.5 wt-% to about 20 wt-%, preferably from about 2 wt-% to about 15 wt-%, and most preferably from about 4 wt-% to about 12 wt-%.
The composition used in the method of the invention also includes an oxidizer. Any number of oxidizers may be used as a precursor to the formation of a peroxycarboxylic acid as well as to provide further physical effervescent or agitation action to the composition of the invention. Preferably, the antimicrobial composition of the invention contains hydrogen peroxide. Hydrogen peroxide (H2O2) has a molecular weight of 34.014 and it is a weakly acidic, clear, colorless liquid. The four atoms are covalently bonded in a non-polar structure:
Generally, hydrogen peroxide has a melting point of xe2x88x920.41xc2x0 C., a boiling point of 150.2xc2x0 C., a density at 25xc2x0 C. of 1.4425 grams per cm3, and a viscosity of 1.245 centipoise at 20xc2x0 C.
Hydrogen peroxide in combination with the carboxylic acid and peroxycarboxylic acid provides a surprising level of antimicrobial action against microorganisms, even in the presence of high loadings of organic sediment. Additionally, hydrogen peroxide provides an effervescent action which may irrigate any surface to which it is applied. Hydrogen peroxide works with a mechanical flushing action once applied which further plains the surface of application. An additional advantage of hydrogen peroxide is the food compatibility of this composition upon use and decomposition. For example, combinations of peroxyacetic acid and hydrogen peroxide result in acetic acid, water, and oxygen upon decomposition. All of these constituents are food product compatible. Generally, the concentration of hydrogen peroxide within the composition used in the process of the invention ranges from about 1 wt-% to about 35 wt-%, preferably from about 2 wt-% to about 25 wt-%, and most preferably from about 5 wt-% to about 10 wt-%. This concentration of hydrogen peroxide is most preferred as providing optimal antimicrobial effect.
These concentrations of hydrogen peroxide may be increased or decreased while still remaining within the scope of the present invention. For example, increasing the concentration of hydrogen peroxide may increase the antimicrobial efficacy of the claimed invention. Furthermore, increasing the hydrogen peroxide concentration may reduce the need to stabilize the hydrogen peroxide within the composition. Specifically, increasing the hydrogen peroxide concentration in the composition may provide a composition which has extended shelf life.
In contrast, decreasing the concentration of hydrogen peroxide may decrease the antimicrobial efficacy of the composition and necessitate the use of an increased concentration of carboxylic acid. Moreover, decreasing the concentration of hydrogen peroxide may necessitate the use of some stabilizing agent to ensure that the composition of the present invention will remain stable and efficacious over the intended time period.
In all, altering the concentration of the oxidizing agent will effect the equilibrium mix of the peroxycarboxylic acid used in the invention.
The composition of the invention also includes a carrier. The carrier functions to provide a reaction medium for the solubilization of constituents and the production of peroxycarboxylic acid as well as a medium for the development of an equilibrium mixture of oxidizer, peroxycarboxylic acid, and carboxylic acid. The carrier also functions to deliver and wet the antimicrobial composition of the invention to the intended substrate. To this end, the carrier may contain any component or components which will facilitate the functions. Generally, the carrier consists of water which is an excellent solubilizer and medium for reaction and equilibrium. The carrier may also include any number of constituents such as various organic compounds which facilitate the functions provided above. Organic solvents which have been found useful include simple alkyl alcohols such as ethanol, isopropanol, n-propanol, and the like. Polyols are also useful carriers in accordance with the invention, including propylene glycol, polyethyleneglycol, glycerol, sorbitol, and the like. Any of these compounds may be used singly or in combination with other organic or inorganic constituents or, in combination with water or in mixtures thereof. Preferably, the carrier consists of from about 1 wt-% to about 60 wt-% of an organic solvent.
Generally, the carrier makes up a large portion of the composition of the invention and may essentially be the balance of the composition apart from the active antimicrobial composition adjuvants, and the like. Here again, the carrier concentration and type will depend upon the nature of the composition as a whole, the environmental storage and method of application including concentration of the antimicrobial agent, among other factors. Notably the carrier should be chosen and used at a concentration which does not inhibit the antimicrobial efficacy of the act in the composition of the invention.
B. Adjuvants
The composition of the invention may also optionally include any number of adjuvants which are stable in an oxidizing environment, and add beneficial properties of stability, sequestration, sheeting and rinsing, etc. These adjuvants may be preformulated with the sanitizing agent of the invention or added to the system simultaneously, or even after, the addition of the sanitizing agent of the invention.
The sanitizing agents of the invention may also contain a polyvalent metal complexing or chelating agent that aids in reducing the harmful effects of hardness components and service water and improves product stability. The typically harmful effects of calcium, magnesium, iron, manganese, etc., ions present in service water can interfere with the action of either the washing compositions or rinsing compositions or can tend to decompose the active peroxygen sanitizer materials. The chelating agent or sequestering agent can effectively complex and remove such ions from inappropriate interaction with active ingredients thus increasing sanitizing agent performance.
Both organic and inorganic chelating agents may be used. Inorganic chelating agents include such compounds as sodium tripolyphosphate and other higher linear and cyclic polyphosphate species. Organic chelating agents include both polymeric and small molecule chelating agents. Polymeric chelating agents commonly comprise polyanionic compositions such as polyacrylic acid compounds. Amino phosphates and phosphonates are also suitable for use as chelating agents in the compositions of the invention and include ethylene diamine (tetramethylene phosphonates), nitrilotrismethylene phosphates, diethylenetriamine (pentamethylene phosphonates). These amino phosphonates commonly contain alkyl or alkaline groups with less than 8 carbon atoms.
Preferred chelating agents for use in this invention include improved food additive chelating agents such as disodium salts of ethylene diamine tetraacetic acid or the well known phosphonates sold in the form of DEQUEST(copyright) materials, for example, 1-hydroxyethylidene-1,1-iphosphonic acid, etc. The phosphonic acid may also comprise a low molecular weight phosphonopolycarboxylic acid such as one having about 24 carboxylic acid moieties and about 1-3 phosphonic acid groups. Such acids include 1-phosphono-1-methylsuccinic acid, phosphonosuccinic acid and 2-phosphonobutane-1,2,4tricarboxylic acid. Another organic phosphonic acid is (CH3C(PO3H2)2OH), available from Monsanto Industrial Chemicals Co., St. Louis, Mo., as DEQUEST(copyright) 2010, (which is a 58-62% aqueous solution; amino (tri(methylenephosphonic acid)] (N[CH2PO3H]3), available from Monsanto as DEQUEST(copyright) 2000, as a 50% aqueous solution; ethylenediamine [tetra(methylenephosphonic acid)] available from Monsanto as DEQUEST(copyright) 2041, as a 90% solid acid product; and 2-phosphonobutane-1,2,4-tricarboxylic acid available from Mobay Chemical Corporation, Inorganic Chemicals Division, Pittsburgh, Pa., as Bayhibit AM, as a 45-50% aqueous solution.
The above-mentioned phosphonic acids can also be used in the form of water soluble acid salts, particularly the alkali metal salts, such as sodium or potassium; the ammonium salts or the alkylol amine salts where the alkylol has 2 to 3 carbon atoms, such as mono-, di-, or triethanolamine salts. If desired, mixtures of the individual phosphonic acids or their acid salts can also be used.
The concentration of chelating agent useful in the present invention generally ranges from about 0.01 to about 10 wt-%, preferably from about 0.1 to about 5 wt-%, most preferably from about 0.5 to about 2 wt-%.
The sanitizing agent of the invention may also include a hydrotrope coupler or solubilizer. Such materials can be used to ensure that the composition remains phase stable and in a single highly active aqueous form. Such hydrotrope solubilizers or couplers can be used at compositions which maintain phase stability but do not result in unwanted compositional interaction.
Representative classes of hydrotrope solubilizers or coupling agents include an anionic surfactant such as an alkyl sulfate, an alkyl or alkane sulfonate, a linear alkyl benzene or naphthalene sulfonate, a secondary alkane sulfonate, alkyl ether sulfate or sulfonate, an alkyl phosphate or phosphonate, dialkyl sulfosuccinic acid ester, sugar esters (e.g., sorbitan esters) and a C8-10 alkyl glucoside.
Preferred coupling agents for use in the rinse agents of the invention include n-octane sulfonate and aromatic sulfonates such as an alkyl benzene sulfonate (e.g., sodium xylene sulfonate or naphthalene sulfonate). Many hydrotrope solubilizers independently exhibit some degree of antimicrobial activity at low pH. Such action adds to the efficacy of the invention but is not a primary criterion used in selecting an appropriate solubilizing agent. Since the presence of the peroxycarboxylic acid material in the proteinated neutral state provides beneficial biocidal or sanitizing activity, the coupling agent should be selected not for its independent antimicrobial activity but for its ability to provide effective single phase composition stability in the presence of substantially insoluble peroxycarboxylic acid materials and the more soluble compositions of the invention.
Generally, any number of surfactants may be used consistent with the purpose of this constituent.
Anionic surfactants useful with the invention include alkyl carboxylates, linear alkylbenzene sulfonates, paraffin sulfonates and secondary n-alkane sulfonates, sulfosuccinate esters and sulfated linear alcohols.
Zwitterionic or amphoteric surfactants useful with the invention include xcex2-N-alkylaminopropionic acids, n-alkyl-xcex2-iminodipropionic acids, imidazoline carboxylates, n-alky-Iletaines, amine oxides, sulfobetaines and sultaines.
Nonionic surfactants useful in the context of this invention are generally polyether (also known as polyalkylene oxide, polyoxyalkylene or polyalkylene glycol) compounds. More particularly, the polyether compounds are generally polyoxypropylene or polyoxyethylene glycol compounds. Typically, the surfactants useful in the context of this invention are synthetic organic polyoxypropylene (PO)-polyoxyethylene (EO) block copolymers. These surfactants have a diblock polymer comprising an EO block and a PO block, a center block of polyoxypropylene units (PO), and having blocks of polyoxyethylene grated onto the polyoxypropylene unit or a center block of EO with attached PO blocks. Further, this surfactant can have further blocks of either polyoxyethylene or polyoxypropylene in the molecule. The average molecular weight of useful surfactants ranges from about 1000 to about 40,000 and the weight percent content of ethylene oxide ranges from about 10-80% by weight.
Also useful in the context of this invention are surfactants including alcohol alkoxylates having EO, PO and BO blocks. Straight chain primary aliphatic alcohol alkoxylates can be particularly useful as sheeting agents. Such alkoxylates are also available from several sources including BASF Wyandotte where they are known as xe2x80x9cPlurafacxe2x80x9d surfactants. A particular group of alcohol alkoxylates found to be useful are those having the general formula R-(EO)m-(PO)n. wherein m is an integer of about 2-10 and n is an integer from about 2-20. R can be any suitable radical such as a straight chain alkyl group having from about 6-20 carbon atoms.
Other useful nonionic surfactants of the invention include capped aliphatic alcohol alkoxylates. These end caps include but are not limited to methyl, ethyl, propyl, butyl, benzyl and chlorine. Preferably, such surfactants have a molecular weight of about 400 to 10,000. Capping improves the compatibility between the nonionic and the oxidizers hydrogen peroxide and peroxycarboxylic acid, when formulated into a single composition. Other useful nonionic surfactants are alkylpolyglycosides.
Another useful nonionic surfactant of the invention is a fatty acid alkoxylate wherein the surfactant comprises a fatty acid moiety with an ester group comprising a block of EO, a block of PO or a mixed block or heteric group. The molecular weights of such surfactants range from about 400 to about 10,000, a preferred surfactant has an EO content of about 30 to 50 wt-% and wherein the fatty acid moiety contains from about 8 to about 18 carbon atoms.
Similarly, alkyl phenol alkoxylates have also been found usefull in the invention. Such surfactants can be made from an alkyl phenol moiety having an alkyl group with 4 to about 18 carbon atoms, can contain an ethylene oxide block, a propylene oxide block or a mixed ethylene oxide, propylene oxide block or heteric polymer moiety. Preferably such surfactants have a molecular weight of about 400 to about 10,000 and have from about 5 to about 20 units of ethylene oxide, propylene oxide or mixtures thereof.
The concentration of hydrotrope useful in the present invention generally ranges from about 0.1 to about 20 wt-%, preferably from about 0.5 to about 10 wt-%, most preferably from about 1 to about 4 wt-%.
Thickeners useful in the present invention are those which do not leave contaminating residue on the surface of application, i.e., constituents which are incompatible with food or other sensitive products in contact areas.
Generally, thickeners which may be used in the present invention include natural gums such as xanthan gum. Also useful in the present invention are cellulosic polymers, such as carboxymethyl cellulose. Generally, the concentration of thickener use in the present invention will be dictated by the desired viscosity within the final composition. However, as a general guideline, viscosity of thickener within the present composition ranges from about 0.1 wt-% to about 1.5 wt-%, preferably from about 0.1 wt-% to about 1.0 wt-%, and most preferably from about 0.1 wt-% to about 0.5 wt-%.
C. Formulation
The compositions of the invention can be formulated by combining the sanitizing agent materials including other adjuvant components with the materials that form the sanitizer composition, the carboxylic acid or acid blend, hydrogen peroxide and optionally, hydrotrope solubilizer.
The compositions can also be formulated with preformed peroxycarboxylic acids. The preferred compositions of the invention can be made by mixing the carboxylic acid or mixture thereof with an optional hydrotrope solubilizer or coupler, reacting the mixture with hydrogen peroxide and then adding the balance of required ingredients to provide rinsing and sanitizing action.
A stable equilibrium mixture is produced containing the carboxylic acid or blend with hydrogen peroxide and allowing the mixture to stand for 1-7 days at 15xc2x0 C. or more. With this preparatory method, an equilibrium mixture will be formed containing an amount of hydrogen peroxide, unoxidized acid, oxidized or peroxycarboxylic acid and typically unmodified couplers, solubilizer, or stabilizers.
D. Use Compositions
The invention contemplates a concentrate composition which is diluted to a use solution prior to its utilization as a sanitizer. Primarily for reasons of economics, the concentrate would normally be marketed and an end user would preferably dilute the concentrate with water or an aqueous diluent to a use solution.
The general constituent concentrations of the sanitizing concentrate formulated in accordance with the invention may be found in Table 1:
The level of active components in the concentrate composition is dependent on the intended dilution factor and the desired activity of the peroxycarboxylic acid compound and the carboxylic acid.
Generally, a dilution of about 1 fluid ounce to about 0.5 to 10.0 gallons of water is used for aqueous antimicrobial sanitizing solutions. The composition shown in the preferred column of the Table 1 above would be used in a range from about 12.8 fluid ounce per gallon water to about 1 fluid ounce per 780 gallons of water depending on the desired level of peroxycarboxylic acid and concentration of the peroxycarboxylic acid in the product concentrate.
Higher use dilutions can be employed if elevated use temperature (greater than 25xc2x0 C.) or extended exposure time (greater than 30 seconds) can be employed. In the typical use locus, the concentrate is diluted with a major proportion of water and used for sanitizing using commonly available tap or service water mixing the materials at a dilution ratio of about 0.1 to about 2 ounces of concentrate per gallon of water.
Aqueous antimicrobial sanitizing use solutions can include at least about 2 ppm, preferably about 10 to about 500 ppm, and more preferably about 100 to about 250 parts per million of the peroxycarboxylic acid material; about 20 ppm to about 10,000 ppm, and preferably about 50 ppm to about 1,000 ppm of carboxylic acid; and about 10 to about 1,000 ppm of hydrogen peroxide. The aqueous use solution can further include at least about 50 ppm, preferably about 500 ppm of the hydrotrope solubilizer, and have a pH in the use solution in the range of about 1 to about 11 preferably about 2 to about 10.
E. Method of Use
During processing of the carcass meat, the carcasses can be contacted with the compositions of the invention in any mode be that insures good contact between the carcass and the composition and at least some minimal mechanical work to result in at least a one log 10 reduction, preferably at least a two log10 reduction and more preferably a three log10 reduction in the resident microbial preparation. A five log10 reduction in 30 seconds is a sanitizing treatment.
The invention is applicable to a wide range of possible animal carcasses. For example, the antimicrobial compositions of the invention can be used on muscle meats including beef, pork, veal, buffalo or lamb, sea food including scallops, shrimp, crab, octopus, mussels, squid or lobster and poultry including chicken, turkey, ostrich, game hen, squab or pheasant.
A preferred mode is a pressure spray with the sanitizing solution of the invention. During application of the spray solution on the carcasses, the surface of the carcasses can be moved with mechanical action, preferably agitated, rubbed, brushed, etc. Agitation may be by physical scrubbing of the carcasses, through the action of the spray solution under pressure or by other means. The agitation increases the efficacy of the spray solution in killing micro-organisms, perhaps due to better exposure of the solution into the crevasses or small colonies containing the micro-organisms. The spray solution, before application, may also be heated to a temperature of about 15 to 20xc2x0 C., preferably about 20 to 50xc2x0 C. to increase efficacy. After a sufficient amount of time to kill the micro-organisms on the carcasses, the spray solution may be rinsed off the animal carcasses.
Application of the material by spray means can be accomplished using a manual spray wand application, an automatic spray of carcasses moving along a production line using multiple spray heads to ensure complete contact or other spray means. One preferred automatic spray application involves the use of a spray booth. The spray booth substantially confines the sprayed composition to within the parameter of the booth. The production line moves the carcass through the entryway into the spray booth in which the carcass is sprayed on all its exterior surfaces with sprays within the booth. After a complete coverage of the material and drainage of the material from the carcass within the booth, the carcass can then exit the booth in a fully treated form. The spray booth can comprises steam jets that can be used to apply the antimicrobial compositions of the invention. These steam jets can be used in combination with cooling water to ensure that the treatment reaching the carcass surface is less than 65xc2x0 C., preferably less than 60xc2x0 C. The temperature of the spray on the carcass is important to ensure that the carcass meat is not substantially altered (cooked) by the temperature of the spray. The spray pattern can be virtually any useful spray pattern.
The spray can comprise a fogged material that leaves a fogging apparatus as a dispersion of fog particles in a continuous atmosphere. Such a spray has no defined pattern. The spray can have a pattern such as a conical spray in which the angle between the perimeter of the spray ranges from less than 180xc2x0 to about 5xc2x0. Other spray patterns can also be useful. We have found that one preferred spray pattern involves a xe2x80x9cfanxe2x80x9d spray pattern in which the spray exits the spray head in a substantially planar form and the angle between the extent of the planar spray from edge to edge is about 20xc2x0 or less, preferably about 15xc2x0 or less. We have found that such a spray is preferred due to the increased mechanical action and efficiency of antimicrobial composition add on to the carcass. When such a narrow angle fan spray is used in a spray cabinet enclosure to treat the carcasses, we have found that the optimum distance between the spray head and the carcass is less than about 100 centimeters, preferably about 20 to 80 centimeters, most preferably about 30 to 50 centimeters. Such a configuration efficiently transfers antimicrobial material to the carcass for efficient reduction of the microbial populations.
There are a number of parameters which need to be considered if spraying is the application method of choice. The first parameter to determine is the pressure at which the composition is sprayed onto the carcass. While spray pressures as low as about 25 psi (gauge) can be used with some valuable results, a higher spray pressure, greater than about 25, 50, 100, 150 psi and more preferably greater than about 200 psi, are effective in reducing the microbial populations due to the mechanical action of the spray on the carcass surface and on the microbial population remaining on the surface of the carcass. The spray action is best at temperatures less than 65xc2x0 C. While a composition comprising lactic acid has been found to be most effective at low pressure, it has been discovered that equal, if not greater antimicrobial efficacy can be obtained by eliminating the lactic acid and merely increasing the spray application pressure. Further, if increased spray pressures are used, the antimicrobial composition can be applied at lower temperatures, potentially resulting in substantial energy savings. Of course there appears to be a relationship between application spray duration and antimicrobial efficacy. While spray durations of as little as about 10 seconds can be used, it has been discovered that a preferred spray duration is from about 10 to about 30 seconds. Without wishing to be limited by theory, the increased antimicrobial efficacy resulting from the use of the higher spray pressures is believed to be due to an improvement in penetrating the surface of the carcass, particularly an increased ability to reach into creases and crevices on the surface of the carcass.
During processing of the carcass meat, the carcasses may also be immersed into a tank containing a quantity of sanitizing solution. The sanitizing solution is preferably agitated to increase the efficacy of the solution and the speed in which the solution kills micro-organisms attached to the carcasses. Agitation can be obtained through conventional means including through ultrasonic means, aeration by bubbling air through the solution or by mechanical means, such as strainers, paddles, brushes, or pump driven liquid jets. The sanitizing solution may also be heated to increase the efficacy of the solution in killing micro-organisms. It is preferable that the carcasses be immersed in the sanitizing solution after the carcasses have been eviscerated and before any cooling process such as a chiller tank or a chill water spray.
In another alternative embodiment of the present invention, the carcasses may be treated with a foaming version of the composition. The foam may be prepared by mixing foaming surfactants with the sanitizing solution at time of use. The foaming surfactants could be nonionic, anionic or cationic in nature. Examples of useful surfactant types include, but not limited to the following: alcohol ethoxylates, alcohol ethoxylate carboxylate, amine oxides, alkyl sulfates, alkyl ether sulfate, sulfonates, quaternary ammonium compounds, alkyl sarcosines, betaines and alkyl amides. The foaming surfactant is mixed at time of use with the sanitizing solution. Use solution levels of the foaming agents is from about 50 ppm to about 2.0 wt-%. At time of use, compressed air is injected into the mixture, then applied to the carcass surface through a foam application device such as a tank foamer or an aspirated wall mounted foamer.
In another alternative embodiment of the present invention, the carcasses may be treated with a thickened or gelled version of the composition. In the thickened or gelled state the sanitizing solution remains in contact with the carcass surface for longer periods of time, thus increasing the antimicrobial efficacy. The thickened or gelled solution will also adhere to vertical surfaces. The composition or the sanitizing solution may be thickened or gelled using existing technologies such as: xantham gum, polymeric thickeners, cellulose thickeners or the like. Rod micelle forming systems such as amine oxides and anionic counter ions could also be used. The thickeners or gel forming agents can be used either in the concentrated product or mixing with the sanitizing solution, at time of use. Typical use levels of thickeners or gel agents range from about 100 ppm to about 10 wt-%.
In another alternative embodiment of the present invention, the carcasses may be treated with an electrostatically charged spray of the sanitizing solution. The sanitizing solution can be spray applied as a charged droplets by using conventional electrostatic spray technologies including inductively charged methodologies. As charged droplets, the sanitizing solution will be attracted to opposite or differentially charged surfaces such as the surface of the carcass. As a result, more sanitizing solution will be applied to the carcass surface and less solution will miss the intended target, commonly called over-spray. The charged droplets will also provide an evenly distributed solution layer on the carcass surface. The charged droplet size will range from about 10 microns to about 500 microns.
In another alternative embodiment of the present invention, the carcasses may be subjected to a vacuum treatment either before applying the sanitizing solution, during the application of the sanitizing solution or after applying the sanitizing solution. When the carcass is subjected to a vacuum treatment in conjunction with the application of the sanitizing solution, the penetration of the sanitizing solution into the carcass substructure is enhanced. As a result, antimicrobial efficacy is improved. The amount of vacuum utilized is from about 2 inches of Mercury (xe2x80x3Hg) to about 29 inches of Mercury (xe2x80x3Hg).
In another alternative embodiment of the present invention, the carcasses may be subjected to an activating light source following application of the sanitizing solution. The activating light can improve the antimicrobial efficacy of the sanitizing solution. The light source can be ultraviolet, infrared or from the visible spectrum.
The antimicrobial or sanitizing step can optionally be combined with a thermal intervention process which occurs either before, during or after the application of the antimicrobial composition. The thermal intervention process may employ hot water or dry heat. In the case of a hot water thermal process, the carcass is enclosed in a chamber at atmospheric pressure. The chamber is filled with condensing steam (finely divided liquid water) for a short duration, quickly vented, then cooled to prevent browning of the meat carcass. The duration of the steam thermal process may be from about 5 seconds to about 30 seconds. The chamber temperature may reach from about 50xc2x0 C. to about 93xc2x0 C. Similarly with dry heat, the carcass is placed in a chamber into which heated air is directed. The air is heated from about 65xc2x0 C. to about 260xc2x0 C. The carcass is allowed from about 5 to about 30 seconds contact time with the heated air, the chamber is vented and the carcass is cooled.


Doorway or passageway arches and a mold and method for making doorway arches, wherein the arches comprise pre-fabricated plaster, two sides that are substantially perpendicular to each other, a concave arcuate side extending between the sides and flanges extending outward from each side for securing the arch to adjoining walls defining a comer, and the mold comprises a base, at least two perpendicularly disposed slots, at least one slidably insertable and removable board for each slot, a mold projecting upward from said base and having a convex side extending between opposing ends of said boards, flanges disposable along the boards and a volume for receiving a hardening agent, such as plaster.

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A portion of the disclosure of this patent document contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or patent disclosure as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyrights rights whatsoever.
1. Field of the Invention
The present invention relates generally to doorway or passageway arches and a mold and method for making doorway arches, and more particularly, to a pre-fabricated plaster arch having exposed flanges that allow it to be easily installed in any doorway and a mold and method for making plaster arches that allows plaster arches to be completely made prior to installation.
2. Description of the Background Art
The construction of arches in doorways, or passageways, can be tedious, expensive and time-consuming work. In fact, this type of work invariably has to be done by a trained carpenter. The construction of arches typically involves cutting plywood and drywall into the desired semi-circle arched shape, making cross-members (usually from 2xc3x974 studs) for securely joining the plywood in a manner that corresponds to the thickness of the passageway wall, securing the plywood to the cross-members to form the framework, mounting the drywall to the plywood, attaching comer beads, taping all seams, and floating or filling the seams. Some pre-framed arches are known in the art, however, they are not complete. That is, they still require the use of plaster or stucco, drywall, tape, floating and comer beads, and can be difficult to install. There are no known devices, molds or methods that allow a plaster arch to be made before installation so that it only needs to be mounted to the comer of the passageway and made flush with the wall. A pre-fabricated plaster-based arch would help carpenters save time and customers save money and could be installed by non-professionals as well. Consequently, a device or method for simplifying the construction of passageway arches would be well received.
Several arch members and methods for making arches are known in the background art. However, none of these addresses or solves the above-noted problems associated with making and mounting arches. The patent references found fail to disclose important structural elements of the instant invention. For instance, U.S. Pat. No. 1,782,147 discloses a metal arch member for openings comprising a box-like arcuate member that is mounted to a comer of a doorway for adhering plaster. U.S. Pat. No. 1,931,889 discloses a metal cove and bracket for producing an arcuate cove between a wall and ceiling. U.S. Pat. No. 2,344,279 discloses a plastering base comprising a pre-formed base strip for attachment to doorway studs and applying plaster. U.S. Pat. No. 2,442,929 discloses an arch member for openings comprising a support or base adapted to be covered with plaster. U.S. Pat. No. 3,008,273 discloses a hollow preformed arch and method of making the same comprising plasterboard panels and metal comer beads having a plurality of slits for gripping cement. The method generally comprises forming a curved panel by making a plurality of parallel kerf cuts therein, placing the panel over an arcuate form and applying plaster in the kerf cuts. U.S. Pat. No. 4,301,632 discloses a prefabricated full archway module having a pair of parallel upright panels extending between the floor and ceiling with internal braces and modules defining the upper portion of an archway. U.S. Pat. No. 4,400,917 discloses a unitary structure for a full arch-shaped passageway, which is adapted for drywall construction. The unitary structure includes a front panel, a rear panel and an arcuate panel portion therebetween. U.S. Pat. No. 4,601,138 discloses a prefabricated unitary body forming an archway including a comer bead and a recess therefor. U.S. Pat. No. 5,572,834 discloses a prefabricated arch form for use in constructing an archway wherein opposing sheet metal cheek are spaced apart by a curved throat to permit the cheeks to reside between the adjacent wall support and drywall and to fasten drywall. The foregoing art fails to disclose a prefabricated plaster arch or a mold, kit and/or method for making a prefabricated plaster arch as contemplated by the instant invention.
As the above noted art fails to provide a device or method that fills the foregoing gap in the prior art, there exists a need for a prefabricated plaster arch and mold, kit and method for making the same. The instant invention solves this problem by providing a prefabricated plaster arch that is installation ready, and a mold or kit and method for making plaster arches.
Based on the foregoing, it is a primary object of the instant invention to provide a prefabricated plaster arch or semi-arch that is installation ready.
It is an additional object of the instant invention to provide a prefabricated plaster arch or semi-arch that is easy to install and inexpensive.
It is another object of the instant invention to provide a prefabricated plaster arch or semi-arch that can be installed with common fasteners and only requires that the gap between the arch and wall be covered.
It is also an object of the instant invention to provide a mold that facilitates the making of plaster arches or semi-arches.
It is a further object of the instant invention to provide a method for making plaster arches or semi-arches.
In light of these and other objects, the instant invention comprises a prefabricated plaster arch or semi-arch ready for installation in the corner of a passageway, and a mold, kit and method for making a plaster arch. The plaster arch generally comprises two substantially perpendicular leg portions that meet at a common end, a concave arcuate surface between the two free ends of the leg portions and securing tabs extending outward from each leg. The leg portions form a right angle so that the arch fits within the comer of an opening, passageway or any wall and upper horizontal surface, such as a ceiling. The securing tabs are adaptable for securely receiving and/or passing conventional fasteners, such as screws, nails and anchors, that attach the tabs, and hence the arch, to the horizontal ceiling-like surface and vertical wall-like surface forming the opening. A full arch is formed by placing a prefabricated arch in opposing corners. The width of the arch corresponds to the width of the wall, but can vary. The length of the legs can vary to accommodate the desired look of the arch or arches and can be based on the size of the mold. The plaster arch can also include arcuate corner beads set in the plaster. The arcuate corner beads have slits at predetermined distances, such as an inch, to facilitate easy bending and shaping. The securing tabs may be defined by and project out from a securing clamp that provides a surface for the fill to adhere or grip to. The securing clamp is set in the fill and also includes a plaster retaining surface, locking tabs and/or additional reinforcement members extending therefrom plaster to improve the structural integrity of the arch and to prevent removal of the securing clamps and tabs.
The invention also comprises a mold, kit and method for making pre-fabricated doorway arches. The mold generally comprises a main mold body formed by a box-like structure having a bottom panel, at least two substantially perpendicular and removable side panels and one concave and arcuate panel bridging the side panels and defining a chamber therebetween and therein for filling with plaster or plaster-like material. The mold may also include a second set of substantially perpendicular and removable side panels opposing the first set of side panels and a second concave and arcuate panel joining the second set of side panels. The second set of side panels and second arcuate panel define a chamber therebetween and therein such that the mold forms a second arch when the second chamber is filled with plaster or a plaster-like material. The mold of the instant invention can therefore form up to two substantially uniform plaster arches by setting the securing tabs in the voids and filling the chambers with plaster, paste, concrete, stucco, liquid plastic, joint compound or other suitable filler. The side panels are preferably removable from the main body to facilitate convenient removal of the arches once they have set. The side panels may slide within tracks formed in the bottom panel. The mold body also makes it convenient to uniformly and evenly remove excess filler from the chamber(s) with a trowel blade and to set an arcuate corner bead in the fill.
The kit of the invention includes the mold main body, at least two securing tabs and a filler mix for filling the chamber(s). The kit may further include at least one pair of corner beads having slits cut therein for facilitating easy shaping. The main body comprises at least one set of side panels and at least one arcuate panel, but preferably includes two sets of side panels and two arcuate panels. The side panels are preferably removable. The main body may also include a removable top for accessing the chamber(s) when filling and covering the chamber(s) when the fill is setting and curing. The mold and kit may also include a retaining strap for holding the side panels in place.
The method of making prefabricated plaster arches generally comprise setting up the mold, filling at least one chamber in the mold with a suitable fill, leveling the fill, allowing the fill to set, removing the side panels and removing the arch or arches from the mold. The mold is set up by securely installing or mounting the side panels, setting the arcuate panels if not already fixed to the bottom panel, and setting and orienting the securing clamps in the chambers adjacent the side panels. The arches are then made by filling the chamber or chambers with a suitable fill, leveling the fill with a trowel or other suitable instrument, allowing the fill to set and cure, removing the side panels and removing the arch or arches once the fill has set or cured. The method may also include securing a strap around the outside of the mold to secure the side panels and/or placing a first corner bead along the bottom of the arcuate panel before filling and placing a second comer bead along the top of the arcuate panel after filling the chamber or chambers. The method of the invention may further include installation of at least one arch or two arches, which comprises the steps of aligning the plaster arch in the desired corner of the desired opening, passing or forcing at least one fastener through each securing tab into the corresponding wall surface behind the securing tab, filling or concealing the seams between the arch and wall/ceiling surface with a joint compound, sanding or texturing the surface smooth and painting the arch.
In accordance with these and other objects, which will become apparent hereinafter, the instant invention will now be described with particular reference to the accompanying drawings.

Arch mold apparatus and method for making arches


The invention relates to a nanocomposite for thermal insulation especially for fireproofing purposes, which can be obtained by combining (A) at least 35 wt. % of nanoscaled, optionally surface-modified particles of an inorganic compound; (B) 10-60 wt. % of a compound with at least two functional groups which can react and/or interact with the surface groups of nanoscaled particles (A), (C) 1-40 wt. % of water and/or an organic solvent which has no functional groups or only one which is defined in (B), wherein the above-mentioned percentages relate to the sum of components (A), (B) and (C), and (D)=0-10 wt. % (based on the nanocomposite) of additives.

The present invention relates to a nanocomposite for thermal insulation (e.g., fireproofing), in particular, to a preferably transparent nanocomposite that is suitable as a filler for insulation glass assemblies.
Particularly when in contact with their solution phase, known solvent-containing inorganic gels show ageing phenomena that manifest themselves in shrinking in combination with haze, blistering as well as possibly cracking. Said signs of ageing are often summarized under the term syneresis, and in the literature they are explained by progressive condensation reactions and phase separation.
A gelled dispersion of SiO2 particles in water, for example, can be prepared by concentrating diluted colloidal silica sol solutions. Upon gelation, the individual SiO2 particles initially develop hydrogen bonding between them until Sixe2x80x94OH groups condense to form Sixe2x80x94Oxe2x80x94Si bonds that cannot be cleaved anymore. Due to said rigid Sixe2x80x94Oxe2x80x94Si bonds the gel becomes increasingly brittle and finally breaks under the influence of the capillary forces of the contained solvent and due to tensile stress caused by the shrinkage of the gel body.
It is known that reactive groups can be shielded by surface charges so that said syneresis-active groups are separated from each other. A well-known example thereof is the stabilization of SiO2 with bases such as tetramethylammonium hydroxide. Said surface modification by charges is effective in preventing syneresis, however at the expense of a lack of immobilization since there is not sufficient interaction between the particles. Additionally, only relatively diluted solutions can be prepared in this manner since, if the particles come too close to each other, the shielding by charges breaks and a spontaneous gel formation occurs, resulting in a loss of the blocking of said syneresis.
For certain applications, e.g., as transparent filling between (fire protection) panes, it is necessary to employ gels which stay clear, without the ageing phenomena mentioned above, for extended periods of time. It is also important that said gels exactly maintain their shape when being filled into, e.g., spaces of complex shape in door or wall units made of different materials. Here it is also of particular importance that even at relatively high solids contents, no ageing phenomena due to solvents may occur. This is difficult because the natural ageing process via solution phases, which proceeds according to the Ostwald mechanism, usually cannot be avoided. However, high solids contents are necessary if such systems are to be used as heat protection. Upon the action of heat a foam having fine pores which acts as insulation is formed, as is known in the case of waterglass. A sufficiently high insulation effect as it is, e.g., required in the case of a fire (see, e.g., DIN 4102) can in turn only be realized by very thick fillings or multiple pane assemblies, which result in a very high weight of the system and thus limit the possible applications thereof.
The present invention, therefore, was based on the problem of providing gel systems which make it possible to obtain a sufficiently high solids content, while being absolutely free of syneresis, as well as layer thicknesses (as heat protection) which are significantly below the present state of the art and also provide long-term transparency, which is particularly indispensable in the case of transparent walls.
It has now surprisingly been found that transparent, solid gel materials which do not show ageing phenomena can be prepared by combining nanoscaled particles of inorganic solids with specific organic compounds which shield the groups that are responsible for said syneresis but at the same time develop sufficiently strong bonding forces which are necessary to form a mechanically stable gel body.
Due to the use of particles in the nm range, light scattering is so minimal that sufficient transparency can be ensured. Furthermore, the matrix structure at the interface with the particle is altered and, due to its high proportion, plays a decisive role in the overall properties of the system.
By employing the principle described above, solid and colorless nanocomposite gels which are stable against syneresis may thus be prepared by dispersing inorganic (preferably oxidic) particles in the presence of suitable substances which, on the one hand, protect syneresis-active groups of said colloidal particles and, on the other hand, still effect a certain degree of crosslinking of the particles.
Thus, an object of the present invention is a nanocomposite for thermal insulation, said nanocomposite being obtainable by combining
(A) at least 35% by wt. of nanoscaled, optionally surface-modified particles of inorganic compound;
(B) 10-60% by wt. of compound having at least two functional groups capable of reacting and/or interacting with the surface groups of said nanoscaled particles (A);
(C) 1-40% by wt. of water and/or inorganic solvent which has no or only one functional group as defined above under (B); the above percentages being based on the sum of said components (A), (B) and (C); as well as
(D) 0-10% by wt., based on said nanocomposite, of additives.
Preferably, the nanocomposite just defined is a transparent material which in its final state is present as a rigid (solidified), solid gel.
In the following, the materials constituting the nanocomposite according to the present invention will be described in more detail.
Component (A) consists of nanoscaled particles of inorganic compound. As used in the present specification and in the claims, the term xe2x80x9cnanoscaled particlesxe2x80x9d refers to particles having an (average) particle size of up to 200 nm, preferably up to 100 nm and particularly up to 50 nm. A particularly preferred particle size ranges from 1-20 nm. For producing said nanocomposite said particles are to be employed in an amount of at least 35%, preferably at least 40%, and particularly at least 45% by wt., based on said components (A), (B) and (C).
Generally, said particles are particles of inorganic oxidic compounds, particularly of oxides of the elements aluminum, silicon, phosphorus, boron, tin, zinc, titanium, zirconium, tungsten, and the alkali and alkaline earth metals as well as of the mixed oxides of any of the oxides just mentioned, (mixed) oxides of Si, Al, Ti and/or Zr being preferred, and SiO2 and mixed oxides thereof being particularly preferred. However, according to the present invention, inorganic compounds different from oxides, such as carbides, nitrides, silicides, borides and the like, may also be employed.
Said particles may either be employed as such or may also only be formed in situ by suitable processes (well-known to the person skilled in the art).
Furthermore, said particles may optionally be surface-modified. The surface modification of nanoscaled (particularly oxidic) particles is known from the prior art and described, e.g., in DE-A-42 12 633.
As described above, component (B) of the nanocomposite of the present invention serves to shield said nanoscaled particles of component (A) in a manner such that, on the one hand, ageing phenomena due to interparticular reactions may be avoided in said nanocomposite and, on the other hand, the particles will still be sufficiently bonded to each other (crosslinked) so that a solid, mechanically stable gel body is provided.
Component (B) accounts for 10 to 60% by wt., based on the components (A), (B) and (C) of the nanocomposite of the present invention. Preferably, component (B) is employed in an amount of from 15 to 45% and particularly 20 to 35% by wt., 20 to 30% by wt. of component (B) being particularly preferred.
Component (B) consists of one or more, particularly one, compound (preferably of organic or inorganic/organic nature) having at least two, preferably at least three (and in most cases less than 50) functional groups capable of reacting and/or interacting with surface groups present on the surface of said nanoscaled particles (A). The surface groups of said nanoscaled particles (A) are either those which are present due to the inorganic material constituting said particles (e.g., hydroxy groups), or those which have been provided on the particle surface by a surface modification of said inorganic particles in a subsequent step.
The reaction of said functional groups of the compounds of component (B) with said surface groups of the nanoscaled particles (A) may be a conventional reaction giving rise to covalent or ionic bonds and complex bonding, respectively. Merely for exemplary purposes, the condensation reaction of hydroxy groups with liberation of water or the reaction between hydroxy group and carboxy group may be mentioned here. In the present context, the term xe2x80x9cinteractionxe2x80x9d is to denote any interaction between functional groups of compounds (B) with the surface groups of the nanoscaled particles (A), which interaction results in the functional groups of said compounds (B) and the surface groups of said nanoscaled particles (A) being in permanent immediate proximity to each other without one of the above-mentioned (covalent, ionic or coordination) bonds being observable. In this context, hydrogen bonding and van der Waals or donor-acceptor interactions may be mentioned as examples.
The functional groups of the compounds (B) are preferably those selected from the groups consisting of xe2x80x94OH (including xe2x80x94Sixe2x80x94OH), xe2x80x94SH, xe2x80x94NH2, xe2x80x94NHR, xe2x80x94NR2 (including xe2x80x94CONH2, xe2x80x94CONHR, xe2x80x94CONR2), xe2x80x94NR3+Xxe2x88x92, xe2x80x94COOH, xe2x80x94COOR, xe2x80x94COR, xe2x80x94SiOR and xe2x80x94CSR. A compound (B) may, of course, have two (or more) identical functional groups or functional groups which are different from each other. Also, one or more of said functional group(s) may, for example, be an (activated) Cxe2x80x94C double bond (e.g. of a (meth)acrylic compound).
In the formula just given, R represents an optionally substituted hydrocarbyl group, e.g., an alkyl, aryl, alkenyl, alkaryl and aralkyl group, preferably having up to 20, particularly up to 10 carbon atoms, such as, e.g., methyl, ethyl, propyl, butyl, vinyl, allyl, phenyl, benzyl, tolyl and naphthyl. If two ore more radicals R are present in a group said radicals may be the same or different. Preferably, R is a C1-4 alkyl group. X31  represents an inorganic or organic anion such as, e.g., halide (particularly chloride, bromide and iodide), sulphate, nitrate, phosphate, hydroxide, formate, acetate, propionate and oxalate.
Preferred classes of compounds for component (B) are polyols, alkanolamines, polyamines, polytetraalkylammonium salts and mixtures thereof. Polyols having 3 or more hydroxyl groups are particularly preferred.
Specific examples of compounds (B) which may be employed according to the present invention are glycerol, ethyleneglycol, polyethyleneglycol, trimethylolpropane, pentaerythritol, sorbitol, polyvinylalcohol, monoethanolamine, diethanolamine, triethanolamine, ethylenediamine, diethylenetriamine, polytetraalkylammonium halides (particularly polytetramethylammonium chloride and bromide), (meth)acrylic acid, (meth)acrylic amide and mixtures of said compounds. Among said compounds glycerol, sorbitol and pentaerythritol are preferred. Glycerol is particularly preferred.
Naturally, compound (B) should be a compound that is either liquid at room temperature or is at least sufficiently soluble in component (C).
Component (C), employed according to the present invention, will be employed in an amount of 1-40%, preferably 10-35% and particularly 15-30% by wt. A particularly preferred range for component (C) is 20-25% by wt.
Component (C) may consist of water, of one or more organic solvents or of water and one or more water-miscible organic solvents. Preferably it consists of at least 50% by wt., and particularly 90% by wt. water, the sole use of water as component (C) being particularly preferred. If an organic solvent is employed as component (C) or as constituent thereof, said solvent has at the most one of the functional groups defined for component (B).
As exemplary solvents suitable for said component (C) there may be mentioned monoalcohols (e.g., having 1 to 4 carbon atoms such as methanol, ethanol and propanol), monocarboxylic acids (preferably having 1 to 4 carbon atoms such as formic acid, acidic acid and propionic acid), carboxylic anhydrides (such as acetic anhydride), esters (preferably having a total of 2 to 6 carbon atoms such as ethyl acetate), ethers (preferably having 2 to 6 carbon atoms such as dimethylether and diethylether), monoamines (primary, secondary and tertiary, preferably having up to 6 carbon atoms, such as diethylamine and triethylamine), monomercaptanes (such as ethanethiol and propanethiol). It is, of course, possible to also use mixtures of compounds which belong to the same class of compounds (e.g., two alcohols) or to different types of compounds. Particularly preferred organic solvents for use as and in component (C), respectively, are alkanols such as methanol and ethanol.
Component (D) optionally used for the production of the nanocomposite according to the present invention is used in an amount of at the most 10%, preferably at the most 5% and, particularly, at the most 3% by wt., based on the entire nanocomposite. Preferably component (D) will not be employed. If component (D) is made use of, the additives consist of additives that are conventional for such purposes such as, e.g., conventional stabilizers for said component (A), urea, metal colloids, dyes (e.g., phthalocyanine dyes, photochromic or thermochromic dyes, etc.).
The nanocomposite according to the present invention can simply be prepared by combining and mixing components (A), (B) and (C) (as well as optionally (D)) in any order (and preferably at ambient temperature).
If the nanocomposite is, e.g., to be used as filling for insulation glass panes it is preferably filled into the space intended therefor as soon as possible after said components (A) to (D) have been combined, and is then allowed to cure (solidify to form a gel) within said space. The curing process may take place at room temperature but is strongly accelerated at elevated temperature (e.g., up to 80xc2x0 C.).
Experimentally it was found that the nanocomposite according to the present invention is capable of providing a mechanically stable, transparent and hard gel body which, even after more than 60 days of accelerated ageing test at 80xc2x0 C. (estimation for a term of 10 years of guarantee), does not show any of the known syneresis phenomena such as blisters, haze, shrinking or phase separation, and which, upon heating, results in a dense microstructure having fine pores that ensures excellent heat protection. For example, a fireproofing corresponding to classification F-30 can be achieved with a gel filling having a thickness of only 8 mm in a conventional insulation glass assembly having thermally pre-stressed panes of a thickness of 5 mm. With gels of the prior art this can only be achieved with multiple pane assemblies and gel fillings, respectively having a thickness of 12 to 15 mm.
Furthermore, at least a part of the nanocomposites according to the present invention shows thermotropic properties (due to the reversible agglomeration of the nanoscaled particles (A) to form larger, light-scattering particles upon heating, which agglomeration results in the nanocomposites taking on a white color). This affords an additional contribution to fireproofing since the penetration of radiation heat through the nanocomposite is prevented and hindered, respectively.
The nanocomposite according the present invention can be employed in many fields, e.g., as filling for spaces between building components made of glass (particularly transparent insulation glass assemblies) or plastics, metal, wood, gypsum plaster, fermacel, presspahn, ceramics, natural or artificial stone, as well as in electrical cables for fire protection purposes. It may also be used as a coating composition for building components and is suitable for the production of thermally and mechanically stable foams in the form of, e.g., bulk materials or molded parts.
The present nanocomposite may also be used as a blend with pigments or (organic or inorganic, e.g., fibrous, pulverulent or plate-like) coarser, non-nanoscaled aggregates such as mica pigments, iron oxides, wood flour, glass fibers, metal fibers, carbon fibers, sands, clays and bentonite if the transparency of the materials obtainable thereby is not an issue.

Institut fxc3xcr Neue Materialien gemeinnxc3xctzige GmbH


The invention generally relates to nuclear transport modulators, e.g., CRM1 inhibitors, and more particularly to a compound represented by structural formula I:

Cells from most major human solid and hematologic malignancies exhibit abnormal cellular localization of a variety of oncogenic proteins, tumor suppressor proteins, and cell cycle regulators (Cronshaw et al. 2004, Falini et al 2006). For example, certain p53 mutations lead to localization in the cytoplasm rather than in the nucleus. This results in the loss of normal growth regulation, despite intact tumor suppressor function. In other tumors, wild-type p53 is sequestered in the cytoplasm or rapidly degraded, again leading to loss of its suppressor function. Restoration of appropriate nuclear localization of functional p53 protein can normalize some properties of neoplastic cells (Cai et al. 2008; Hoshino et al. 2008; Lain et al. 1999a; Lain et al. 1999b; Smart et al. 1999), can restore sensitivity of cancer cells to DNA damaging agents (Cai et al. 2008), and can lead to regression of established tumors (Sharpless & DePinho 2007, Xue et al. 2007). Similar data have been obtained for other tumor suppressor proteins such as forkhead (Turner and Sullivan 2008) and c-Abl (Vignari and Wang 2001). In addition, abnormal localization of several tumor suppressor and growth regulatory proteins may be involved in the pathogenesis of autoimmune diseases (Davis 2007, Nakahara 2009). CRM1 inhibition may provide particularly interesting utility in familial cancer syndromes (e.g., Li-Fraumeni Syndrome due to loss of one p53 allele, BRCA1 or 2 cancer syndromes), where specific tumor suppressor proteins (TSP) are deleted or dysfunctional and where increasing TSP levels by systemic (or local) administration of CRM1 inhibitors could help restore normal tumor suppressor function.
Specific proteins and RNAs are carried into and out of the nucleus by specialized transport molecules, which are classified as importins if they transport molecules into the nucleus, and exportins if they transport molecules out of the nucleus (Terry et al. 2007; Sorokin et al. 2007). Proteins that are transported into or out of the nucleus contain nuclear import/localization (NLS) or export (NES) sequences that allow them to interact with the relevant transporters. Chromosomal Region Maintenance 1 (Crm1 or CRM1), which is also called exportin-1 or Xpo1, is a major exportin.
Overexpression of Crm1 has been reported in several tumors, including human ovarian cancer (Noske et al. 2008), cervical cancer (van der Watt et al. 2009), pancreatic cancer (Huang et al. 2009), hepatocellular carcinoma (Pascale et al. 2005) and osteosarcoma (Yao et al. 2009) and is independently correlated with poor clinical outcomes in these tumor types.
Inhibition of Crm1 blocks the exodus of tumor suppressor proteins and/or growth regulators such as p53, c-Abl, p21, p27, pRB, BRCA1, IkB, ICp27, E2F4, KLF5, YAP1, ZAP, KLF5, HDAC4, HDAC5 or forkhead proteins (e.g., FOXO3a) from the nucleus that are associated with gene expression, cell proliferation, angiogenesis and epigenetics. Crm1 inhibitors have been shown to induce apoptosis in cancer cells even in the presence of activating oncogenic or growth stimulating signals, while sparing normal (untransformed) cells. Most studies of Crm1 inhibition have utilized the natural product Crm1 inhibitor Leptomycin B (LMB). LMB itself is highly toxic to neoplastic cells, but poorly tolerated with marked gastrointestinal toxicity in animals (Roberts et al. 1986) and humans (Newlands et al. 1996). Derivatization of LMB to improve drug-like properties leads to compounds that retain antitumor activity and are better tolerated in animal tumor models (Yang et al. 2007, Yang et al. 2008, Mutka et al. 2009). Therefore, nuclear export inhibitors could have beneficial effects in neoplastic and other proliferative disorders.
In addition to tumor suppressor proteins, Crm1 also exports several key proteins that are involved in many inflammatory processes. These include IkB, NF-kB, Cox-2, RXRα, Commd1, HIF1, HMGB1, FOXO, FOXP and others. The nuclear factor kappa B (NF-kB/rel) family of transcriptional activators, named for the discovery that it drives immunoglobulin kappa gene expression, regulate the mRNA expression of variety of genes involved in inflammation, proliferation, immunity and cell survival. Under basal conditions, a protein inhibitor of NF-kB, called IkB, binds to NF-kB in the nucleus and the complex IkB-NF-kB renders the NF-kB transcriptional function inactive. In response to inflammatory stimuli, IkB dissociates from the IkB-NF-kB complex, which releases NF-kB and unmasks its potent transcriptional activity. Many signals that activate NF-kB do so by targeting IkB for proteolysis (phosphorylation of IkB renders it "marked" for ubiquitination and then proteolysis). The nuclear IkBa-NF-kB complex can be exported to the cytoplasm by Crm1 where it dissociates and NF-kB can be reactivated. Ubiquitinated IkB may also dissociate from the NF-kB complex, restoring NF-kB transcriptional activity. Inhibition of Crm1 induced export in human neutrophils and macrophage like cells (U937) by LMB not only results in accumulation of transcriptionally inactive, nuclear IkBa-NF-kB complex but also prevents the initial activation of NF-kB even upon cell stimulation (Ghosh 2008, Huang 2000). In a different study, treatment with LMB inhibited IL-1β induced NF-kB DNA binding (the first step in NF-kB transcriptional activation), IL-8 expression and intercellular adhesion molecule expression in pulmonary microvascular endothelial cells (Walsh 2008). COMMD1 is another nuclear inhibitor of both NF-kB and hypoxia-inducible factor 1 (HIF1) transcriptional activity. Blocking the nuclear export of COMMD1 by inhibiting Crm1 results in increased inhibition of NF-kB and HIF1 transcriptional activity (Muller 2009).
Crm1 also mediates retinoid X receptor α (RXRα) transport. RXRα is highly expressed in the liver and plays a central role in regulating bile acid, cholesterol, fatty acid, steroid and xenobiotic metabolism and homeostasis. During liver inflammation, nuclear RXRα levels are significantly reduced, mainly due to inflammation-mediated nuclear export of RXRα by Crm1. LMB is able to prevent IL-1β induced cytoplasmic increase in RXRα levels in human liver derived cells (Zimmerman 2006).
The role of Crm1-mediated nuclear export in NF-kB, HIF-1 and RXRα signalling suggests that blocking nuclear export can be potentially beneficial in many inflammatory processes across multiple tissues and organs including the vasculature (vasculitis, arteritis, polymyalgia rheumatic, atherosclerosis), dermatologic (see below), rheumatologic (rheumatoid and related arthritis, psoriatic arthritis, spondyloarthropathies, crystal arthropathies, systemic lupus erythematosus, mixed connective tissue disease, myositis syndromes, dermatomyositis, inclusion body myositis, undifferentiated connective tissue disease, Sjogren's syndrome, scleroderma and overlap syndromes, etc.).
CRM1 inhibition affects gene expression by inhibiting/activating a series of transcription factors like ICp27, E2F4, KLF5, YAP1, and ZAP.
Crm1 inhibition has potential therapeutic effects across many dermatologic syndromes including inflammatory dermatoses (atopy, allergic dermatitis, chemical dermatitis, psoriasis), sun-damage (ultraviolet (UV) damage), and infections. CRM1 inhibition, best studied with LMB, showed minimal effects on normal keratinocytes, and exerted anti-inflammatory activity on keratinocytes subjected to UV, TNFα, or other inflammatory stimuli (Kobayashi & Shinkai 2005, Kannan & Jaiswal 2006). Crm1 inhibition also upregulates NRF2 (nuclear factor erythroid-related factor 2) activity, which protects keratinocytes (Schafer et al. 2010, Kannan & Jaiswal 2006) and other cell types (Wang et al. 2009) from oxidative damage. LMB induces apoptosis in keratinocytes infected with oncogenic human papillomavirus (HPV) strains such as HPV 16, but not in uninfected keratinocytes (Jolly et al. 2009).
Crm1 also mediates the transport of key neuroprotectant proteins that may be useful in neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). For example, by (1) forcing nuclear retention of key neuroprotective regulators such as NRF2 (Wang 2009), FOXA2 (Kittappa et al. 2007), parking in neuronal cells, and/or (2) inhibiting NFκB transcriptional activity by sequestering IκB to the nucleus in glial cells, Crm1 inhibition could slow or prevent neuronal cell death found in these disorders. There is also evidence linking abnormal glial cell proliferation to abnormalities in CRM1 levels or CRM1 function (Shen 2008).
Intact nuclear export, primarily mediated through CRM1, is also required for the intact maturation of many viruses. Viruses where nuclear export, and/or CRM1 itself, has been implicated in their lifecycle include human immunodeficiency virus (HIV), adenovirus, simian retrovirus type 1, Borna disease virus, influenza (usual strains as well as H1N1 and avian H5N1 strains), hepatitis B (HBV) and C (HCV) viruses, human papillomavirus (HPV), respiratory syncytial virus (RSV), Dungee, Severe Acute Respiratory Syndrome coronavirus, yellow fever virus, West Nile virus, herpes simplex virus (HSV), cytomegalovirus (CMV), and Merkel cell polyomavirus (MCV). (Bhuvanakantham 2010, Cohen 2010, Whittaker 1998). It is anticipated that additional viral infections reliant on intact nuclear export will be uncovered in the future.
The HIV-1 Rev protein, which traffics through nucleolus and shuttles between the nucleus and cytoplasm, facilitates export of unspliced and singly spliced HIV transcripts containing Rev Response Elements (RRE) RNA by the CRM1 export pathway. Inhibition of Rev-mediated RNA transport using CRM1 inhibitors such as LMB or PKF050-638 can arrest the HIV-1 transcriptional process, inhibit the production of new HIV-1 virions, and thereby reduce HIV-1 levels (Pollard 1998, Daelemans 2002).
Dengue virus (DENV) is the causative agent of the common arthropod-borne viral disease, Dengue fever (DF), and its more severe and potentially deadly Dengue hemorrhagic fever (DHF). DHF appears to be the result of an over exuberant inflammatory response to DENV. NS5 is the largest and most conserved protein of DENV. CRM1 regulates the transport of NS5 from the nucleus to the cytoplasm, where most of the NS5 functions are mediated. Inhibition of CRM1-mediated export of NS5 results in altered kinetics of virus production and reduces induction of the inflammatory chemokine interleukin-8 (IL-8), presenting a new avenue for the treatment of diseases caused by DENV and other medically important flaviviruses including hepatitis C virus (Rawlinson 2009).
Other virus-encoded RNA-binding proteins that use CRM1 to exit the nucleus include the HSV type 1 tegument protein (VP13/14, or hUL47), human CMV protein pp65, the SARS Coronavirus ORF 3b Protein, and the RSV matrix (M) protein (Williams 2008, Sanchez 2007, Freundt 2009, Ghildyal 2009).
Interestingly, many of these viruses are associated with specific types of human cancer including hepatocellular carcinoma (HCC) due to chronic HBV or HCV infection, cervical cancer due to HPV, and Merkel cell carcinoma associated with MCV. CRM1 inhibitors could therefore have beneficial effects on both the viral infectious process as well as on the process of neoplastic transformation due to these viruses.
CRM1 controls the nuclear localization and therefore activity of multiple DNA metabolizing enzymes including histone deacetylases (HDAC), histone acetyltransferases (HAT), and histone methyltransferases (HMT). Suppression of cardiomyocyte hypertrophy with irreversible CRM1 inhibitors has been demonstrated and is believed to be linked to nuclear retention (and activation) of HDAC 5, an enzyme known to suppress a hypertrophic genetic program (Monovich et al. 2009). Thus, CRM1 inhibition may have beneficial effects in hypertrophic syndromes, including certain forms of congestive heart failure and hypertrophic cardiomyopathies.
CRM1 has also been linked to other disorders. Leber's disorder, a hereditary disorder characterized by degeneration of retinal ganglion cells and visual loss, is associated with inaction of the CRM1 switch (Gupta N 2008). There is also evidence linking neurodegenerative disorders to abnormalities in nuclear transport.
To date, however, small-molecule, drug-like Crm1 inhibitors for use in vitro and in vivo are uncommon.

This patent is subject to a terminal disclaimer.

Hydrazide containing nuclear transport modulators and uses thereof

Abstract: or a pharmaceutically acceptable salt thereof, wherein the values and alternative values for the variables are as defined and described herein. The invention also includes the synthesis and use of a compound of structural formula I, or a pharmaceutically acceptable salt or composition thereof, e.g., in the treatment, modulation and/or prevention of physiological conditions associated with CRM1 activity.